We have investigated the infection of human peripheral blood monocyte/macrophages by HIV and ways of inhibiting this process. Monocyte/macrophages were easily infected by the Ba-L strain of HIV, obtained from Drs. Popovic and Gartner. In contrast to other reports which had appeared in the literature, we found that dideoxynucleosides (including AZT, ddC, ddl and ddA) were potent inhibitors of do novo HIV infection in monocyte/macrophages. In regard to AZT, this was surprising, as monocytes have very low levels of thymidine kinase (responsible for catalyzing the first step of AZT phosphorylation) and there were very low levels of AZT-5'-triphosphate in monocytes exposed to AZT. We further found that monocytes have very low levels of thymidine-5'-triphosphate. Thus, the ration of AZT-triphosphate to thymidine-triphosphate is actually higher in monocytes than in T cells, and this can account for its activity. In further experiments, we found that granulocyte-macrophage colony stimulating factor (GM-CSF) and macrophage colony stimulating factor (M-CSF) both enhanced the replication of HIV in monocytes. GM-CSF, however, also stimulates the acti-HIV activity of AZT and other thymidine analogues such as 2',3'-didehydro-2',3'-dideoxythymidine (D4T). In the case of AZT, the increased activity appears to occur because of a combination of increased entry and increased phosphorylation. GM-CSF does not enhance the anti-HIV activity of other dideoxynucleosides such as ddC and ddl. Interestingly, M-CSF does not appear to enhance the anti-HIV activity of AZT or the other dideoxynucleosides. We further explored whether CD4 binding was a necessary component of the entry of HIV into monocytes. Infection of monocytes was inhibited by agents which block gpl2O binding to CD4 such as Leu 3, CD4, or CD4-IgG. We further asked whether this would apply in the presence of enhancing antibodies. Very low concentrations of anti-HIV antibodies were found to enhance infection of monocytes by HIV. However, even under those conditions, infection was blocked by Lau 3 or soluble CD4.